, Volume 52, Issue 7, pp 1308-1314

First online:

Combined analysis of 19 common validated type 2 diabetes susceptibility gene variants shows moderate discriminative value and no evidence of gene–gene interaction

  • T. SparsøAffiliated withSteno Diabetes Center Email author 
  • , N. GrarupAffiliated withSteno Diabetes Center
  • , C. AndreasenAffiliated withSteno Diabetes Center
  • , A. AlbrechtsenAffiliated withDepartment of Biostatistics, University of Copenhagen
  • , J. HolmkvistAffiliated withSteno Diabetes Center
  • , G. AndersenAffiliated withSteno Diabetes Center
  • , T. JørgensenAffiliated withResearch Centre for Prevention and Health, Glostrup University HospitalUniversity of Copenhagen
  • , K. Borch-JohnsenAffiliated withSteno Diabetes CenterUniversity of Aarhus
  • , A. SandbækAffiliated withDepartment of General Practice, Institute of Public Health, Aarhus University
    • , T. LauritzenAffiliated withDepartment of General Practice, Institute of Public Health, Aarhus University
    • , S. MadsbadAffiliated withUniversity of CopenhagenDepartment of Endocrinology, Hvidovre University Hospital
    • , T. HansenAffiliated withSteno Diabetes CenterFaculty of Health Sciences, University of Southern Denmark
    • , O. PedersenAffiliated withSteno Diabetes CenterUniversity of AarhusUniversity of Copenhagen



The list of validated type 2 diabetes susceptibility variants has recently been expanded from three to 19. The variants identified are common and have low penetrance in the general population. The aim of the study is to investigate the combined effect of the 19 variants by applying receiver operating characteristics (ROC) to demonstrate the discriminatory value between glucose-tolerant individuals and type 2 diabetes patients in a cross-sectional population of Danes.


The 19 variants were genotyped in three study populations: the population-based Inter99 study; the ADDITION study; and additional type 2 diabetic patients and glucose-tolerant individuals. The case–control studies involved 4,093 type 2 diabetic patients and 5,302 glucose-tolerant individuals.


Single-variant analyses demonstrated allelic odds ratios ranging from 1.04 (95% CI 0.98–1.11) to 1.33 (95% CI 1.22–1.45). When combining the 19 variants, subgroups with extreme risk profiles showed a threefold difference in the risk of type 2 diabetes (lower 10% carriers with ≤15 risk alleles vs upper 10% carriers with ≥22 risk alleles, OR 2.93 (95% CI 2.38–3.62, p = 1.6 × 10−25). We calculated the area under a ROC curve to estimate the discrimination rate between glucose-tolerant individuals and type 2 diabetes patients based on the 19 variants. We found an area under the ROC curve of 0.60. Two-way gene–gene interaction showed few nominal interaction effects.


Combined analysis of the 19 validated variants enables detection of subgroups at substantially increased risk of type 2 diabetes; however, the discrimination between glucose-tolerant and type 2 diabetes individuals is still too inaccurate to achieve clinical value.


ADDITION Bootstrap Case–control study Genetic association Inter99 Polymorphism ROC Receiver operating characteristic SNP Type 2 diabetes